In healthy adults, angiogenesis is only observed as a physiological phenomenon, such as endometrial maturation associated with the menstrual cycle, or placentation, and is observed during the process of wound healing. In pathologic states, however, angiogenesis is noted in inflammation, rheumatoid arthritis, arteriosclerosis, diabetic retinopathy, or solid carcinoma, and may often lead to the progression or aggravation of these diseases. In solid carcinoma, in particular, cancer tissue grows to a diameter of more than 1 to 2 mm, thus necessitating the formation of nutrient vessels (see non-patent document 1). Furthermore, blood vessels which have infiltrated cancer tissue are deeply involved in cancer metastasis and the prognosis of cancer patients (see non-patent document 2 and non-patent document 3).
Thus, an angiogenesis inhibitor is expected as an anticancer drug with minimal injury to normal tissue, unlike an antineoplastic drug showing cytotoxicity, and is also expected as a postoperative adjuvant therapy because of its effect of suppressing the infiltration and metastasis of cancer cells.
The process of angiogenesis comprises multiple steps, i.e., destruction of the vascular basement membrane by the dysfunction of vascular endothelial cells forming the lining of the blood vessel, spouting and migration of vascular endothelial cells, their proliferation, and tube formation (see non-patent document 4). Vascular endothelial cells involved in angiogenesis are also recruited from vascular endothelial precursor cells existent in the peripheral blood, etc. (see non-patent document 5).
These processes are activated by various angiogenic factors, and many reports have suggested the relationship between VEGF (vascular endothelial growth factor), which is one of the angiogenic factors, and cancer. In recent years, drugs targeting VEGF, or the tyrosine kinase activity of the receptor of VEGF, have been under development (see non-patent document 6 and non-patent document 7).
Many factors to partake in angiogenesis, other than VEGF, are known. An earnest demand for the development of inhibitors, which specifically act on vascular endothelial cells playing a central role in angiogenesis and inhibit their proliferation and function, has been uttered, with the expectation that such inhibitors will be promising as agents for treatment of angiogenic diseases such as cancer.
There have been no reports so far that benzamide derivatives have a specific growth inhibitor action on vascular endothelial cells.
As compounds similar in chemical structure to the benzamide derivatives of the present invention, or their salts, those described in the following documents are named:                Japanese Patent Application Laid-Open No. 2001-526255 (patent document 1, Warner Lambert),        Japanese Patent Application Laid-Open No. 2002-249473 (patent document 2, Ishihara Sangyo Kaisha),        International Publication No. 02/47679 pamphlet (patent document 3, Emory Univ.),        International Publication No. 02/059080 pamphlet (patent document 4, Guilford Pharmaceuticals), and        International Publication No. 93/23357 pamphlet (patent document 5, Res. Corporation Tech. Inc.).However, none of the compounds disclosed in these documents are described or suggested as having an angiogenesis suppressing effect. International Publication No. 02/49632 pamphlet (patent document 6, Institute of Medicinal Molecular Design) discloses compounds, which are similar in chemical structure to the benzamide derivatives of the present invention or their salts, as NFkB activity inhibitors, concretely as IKK inhibitors, and suggests cancer, cancer metastasis, and vascular hyperplastic disease as applications for which such inhibitors are targeted. However, this document does not disclose concrete facts.        
KDR tyrosine kinase inhibitors are named as compounds which act specifically on vascular endothelial cells and inhibit their proliferation (see non-patent document 8, non-patent document 9, and non-patent document 10 for outlines). Of these compounds, SU11248 (Sugen/Pfizer, a compound having a 3-(pyrrol-2-ylmethylidene)-2-indolinone skeleton, see patent document 7), PTK787 (Novartis, a compound having a 1-anilino-(4-pyridylmethyl)-phthalazine skeleton, see patent document 8), ZD6474 (AstraZeneca, a compound having a quinazoline skeleton, see patent document 9), and CP-547.632 (Pfizer, a compound having an isothiazole skeleton, see patent document 10), for example, are at the stage of clinical development as anticancer drugs. However, all of these compounds are different from the present invention in chemical structure and the mechanism of action.                [Patent document 1] Japanese Patent Application Laid-Open No. 2001-526255        [Patent document 2] Japanese Patent Application Laid-Open No. 2002-249473        [Patent document 3] International Publication No. 02/47679 pamphlet        [Patent document 4] International Publication No. 02/59080 pamphlet        [Patent document 5] International Publication No. 93/23357 pamphlet        [Patent document 6] International Publication No. 02/49632 pamphlet        [Patent document 7] International Publication No. 01/37820 pamphlet        [Patent document 8] U.S. Pat. No. 6,258,812        [Patent document 9] International Publication No. 01/32651 pamphlet        [Patent document 10] International Publication No. 99/62890 pamphlet        [Non-patent document 1] Folkmann, J., J. Natul. Cancer Inst., Vol. 82, pages 4-6, 1990        [Non-patent document 2] Weidner, N. et al. N. Engl. J. Med., Vol. 324, pages 1-8, 1991        [Non-patent document 3] Bochner, B. H. et al., J. Natl. Cancer Inst., Vol. 87, pages 1603-1612, 1995        [Non-patent document 4] Klagsbrun, M. and Folkmann, J., Handbook of Experimental Pharmacology, Vol. 95 II, pp. 549-586, 1990        [Non-patent document 5] Asahara, T. et al., Science, Vol. 275, pp. 964-967, 1997        [Non-patent document 6] Kabbinavar, F. et al., J. Clinical Oncology, Vol. 21, pp. 60-65, 2003        [Non-patent document 7] Laird, A. D. and Cherrington, J. M., Expert Opinion Investigational Drugs, Vol. 12, pp. 51-64, 2003        [Non-patent document 8] Boyer, S. J., Current Topics in Medicinal Chemistry, Vol. 2, pp. 973-1000, 2002        [Non-patent document 9] Glade-Bender, J., Kandel, J. J. and Yamashiro, D. J., Expert Opinion on Biological Therapy, Vol. 3, No. 2, pp. 263-276, 2003        [Non-patent document 10] Laird, A. D. and J. M. Cherrington, Expert Opinion Investigational Drugs, Vol. 12, No. 1, pp. 51-64, 2003        